biomarkers | Pharma Strategy Blog

The Use of 18F amyloid imaging in Alzheimers Disease

By MaverickNY on September 30, 2010

Following my live tweets from the AACR molecular diagnostics and cancer therapeutics meeting here in Denver this week, some interesting offline discussions continued. A big focus here was on biomarkers and systems biology. Several readers observed that oncology seems to be ahead compared to other therapy areas.

What is interesting though, is that while oncology is heavy on science, pathways, targeted therapies and multiple mechanisms of actions, it is surprisingly low on predictive biomarkers. It does fare a little better on prognostic biomarkers, granted. In contrast, Alzheimer’s Disease (AD) in many ways, seems to be almost the opposite in that various biomarkers abound, but the field lags in effective targeted drugs and a deep understanding of the underlying biology (relative to oncology that is).

One area where we are likely to see more progress in the near future is in the use of imaging biomarkers for the diagnosis of early Alzheimer’s Disease.

Several companies are currently undertaking clinical trials with imaging biomarkers for AD including Bayer with florbetaben (BAY 94-9172), Avid Radiopharmaceuticals with AV-45 and GE Healthcare with flutemetamol. All three are in phase III development.

Currently the use of Pittsburgh compound B (PiB) in combination with PET allows the imaging of beta-amyloid plaques in the brain that are indicative of AD. However, there are limitations with the use of PiB since it requires use of an on-site cyclotron.

A recent paper by Rik Vandenberghe from the Catholic University Leuven, published in the September edition of the Annals of Neurology caught my attention on this topic. It reported phase 2 trial results from the use of 18F flutemetamol imaging in AD.

In this clinical trial, sponsored by GE Healthcare, blinded visual assessments of 18F- flutemetamol scans were undertaken in 27 subjects with probable early-stage AD and mild cognitive impairment (MCI). The results showed a sensitivity of 93.1% in the ability of the scan to diagnose early AD, as compared to clinical diagnosis as the Standard of Truth (25 out of 27 patients). 18F-flutemetamol was also shown in 20 subjects to have comparable regional standardized uptake value ratios (SUVRs) when compared to 11C-Pittsburgh compound B (11C-PiB). Correlation coefficients ranged from 0.89 to 0.92.

What makes the use of the 18F-labeled PiB derivative interesting is that 18F-flutemamol does not require the use of an on-site cyclotron, unlike 11C-PiB. As the study reports this may make it easier to access PET technology for clinical trials and research into AD.

GE Healthcare have already started a phase 3 trial program with flutemetamol, so it will be interesting to see whether the promising phase 2 results are confirmed when the phase 3 data is available after the study is completed later this year.

Data from other phase III clinical trials make this an area to watch out for. Hopefully the development of imaging biomarkers that allow for early diagnosis, will insoire both more basic research into the underlying biological mechanisms and also stimulate companies develop more targeted drugs for the treatment of what is essentially a horrible, progressive disease.

Photo Credit: Avid Radiopharmaceuticals

Top: Elderly Patient Control

Bottom: 18F AV-45 imaging of amyloid plaque in a patient with Alzheimer’s disease

References:

Vandenberghe, R., Van Laere, K., Ivanoiu, A., Salmon, E., Bastin, C., Triau, E., Hasselbalch, S., Law, I., Andersen, A., Korner, A., Minthon, L., Garraux, G., Nelissen, N., Bormans, G., Buckley, C., Owenius, R., Thurfjell, L., Farrar, G., & Brooks, D. (2010). 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial Annals of Neurology, 68 (3), 319-329 DOI: 10.1002/ana.22068

Biomarkers in cancer research – thoughts from AACR in Denver

By MaverickNY on September 29, 2010

This week I'm adjusting to the high altitude of Denver while at the American Association of Cancer Research (AACR) meeting on molecular diagnostics and cancer therapeutics. It's a great little meeting, networking opportunities are excellent and I'm learning a lot about what new cutting edge ideas are being explored.

I will be doing some highlights from each day series later in the week once I've had time to process all the information, as there is a lot to digest here.

What is interesting though, is to look at big picture trends, both in academia and basic research and also what industry are doing in their research teams, since these ideas may well get incorporated into early phase I clinical trials for validation and pilot purposes. More about this later in the week.

Although a lot of the attendees are from the diagnostics end of the business (either academic or industry), there are quite a few serious researchers and thinkers here too. Gordon Mills from MD Anderson gave one of the best talks I've seen at an opening session in a long while. David Parkinson from Nodality also laid out a strategic and thoughtful overview of how things are currently, and how they will continue to change in cancer research with new approaches.

One thing really struck me here in Denver. While outsiders and FDA become more paranoid about conflicts of interest, it is clear to me that what we actually need is closer and more collaborative relationships between basic and clinical research in order to translate the knowledge and ideas into practice or the clinic more quickly. To do this requires fresh ideas, a fresh approach and better communication and collaboration.

By collaboration, I don't just mean between academia and industry, but between labs and between companies, rather than competition. Increasingly, I'm seeing smart researchers presenting data that was generated on behalf of several groups, often in different cities or even countries, each providing different skills and expertise to the research. This used to happen sporadically between friends and former colleagues, but now it's starting to become more commonplace. It's a good sign and a great way to synergies resources and bring more expertise to projects.

Industry are typically very slow to change and tend to see other companies as rivals rather than for collaborative purposes, which is a great shame given that we're all working towards the same goal: fight cancer.

That said, there are some exciting new, albeit subtle changes afoot. When I think of cancer research, the first two industry research powerhouses I think of are Genentech, who have traditional sought strong relationships with academia and Novartis, who have the Novartis Institute for Biomedical Research (NIBR) and the Genomics Institute of the Novartis Research Foundation (GNF).

More recent examples include Novartis and GSK, who appear to have been collaborating on research projects and the other major one that surprised many was the Merck-Astra-Zeneca hookup on specific, but related compounds with relevant cancer pathways.

Which brings me to Gordon Mills stirring talk on Monday evening. He made the case that this is the time for systems biology to make it's mark. Rather than looking at adding in a targeted therapy eg an EGFR, a MEK or whatever inhibitor (TKI or monoclonal antibody) to shut off one particular piece of a complex pathway, we need to start looking at a broader concept, which he called 'pathwayness'. That is, we have learned that cancer biology is highly complex and shutting off one aberrant or overexpressed protein, won't shut down the whole engine because either the cancer adapts or other parts continue to function and drive the tumour's survival.

For me, what was spooky about this well thought and well argued talk was that it was eerily similar as a concept to what Frank McCormack was describing earlier this year using PI3K as an example. Both McCormack and Mills are probably ahead of their time.

What we need to see is industry listening to what they have to say and start to think more strategically about what to do with all the inhibitors we already have out there for the 12 critical cancer drivers that Bert Vogelstein discussed at AACR earlier this year.

Mills argued cogently that we actually have many of the potential tools we need to take a deeper systems biology approach to personalized medicine and by looking at each patients cancer biology we could potential develop a treatment approach relevant to them. He called this 'listening to what the patient tells us'.

This reminded me that recently, there was an article in Forbes about why personalized medicine is bunk, written by a MD at a VC firm. The article annoyed me, mainly for it's lack of critical thinking, fair balance or even a basic understanding of what is happening in medicine and clinical research. Rather than vent in the comments, I turned up at this AACR meeting and was greatly reassured that cancer research is in good hands and we have many excellent people and resources focused on the whole concept of matching treatment to a patients tumour. It will happen. In many ways the revolution has already begun; we just need to get better at it. Every failure tells us something new and important about what to do next.

We have the tools, but there are also a lot of hurdles and challenges to be addressed along the way, not least the regulatory side of things and a different way of thinking about testing and validating the ideas in clinical trials. The good news is that there is much needed activity going on behind the scenes at the policy level, as witnessed by the Cancer Caucus in DC today, where Harold Varmus is kicking off a new era at the NCI. I'm hopeful that the think tank will have open minds and the passion to change the way we think about cancer research.

Patterns of expression of DNA repair genes and relapse from melanoma

By MaverickNY on August 17, 2010

Someone kindly sent me this paper on how gene expression can be used to track insufficient DNA repair, which can lead to relapse in melanoma, making it potentially useful as both a prognostic and predictive biomarker for the disease. Regular readers will notice that I am slowly changing my opinion of gene expression studies as a result of articles like this one :-).

According to the researchers:

"Over-expression of DNA repair genes was shown to be associated with reduced relapse-free survival, thicker tumors and tumors with higher mitotic rate.

Preliminary data are also reported suggesting that DNA repair genes are overexpressed in tumors from patients who do not respond to chemotherapy."

Resistance to treatment is one of the biggest ongoing problems associated with treatment of melanoma, both with approved therapies and also pipeline drugs, so finding ways to detect it earlier (and the reasons why) would potentially help in sequencing with different drugs.

So what was involved in this study, which is the largest gene expression study to date in melanoma? The authors decided to see whether formalin-fixed tissue analysis would be useful:

"Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer-related genes from these studies were combined for analysis."

The findings were quite interesting.

Basically, the increased expression of DNA repair genes most strongly predicted relapse, and was associated with thicker tumours. Increased expression of RAD51 was the most predictive of relapse-free survival (RFS). In addition, RAD52 and TOP2A were independent predictors of RFS in the analysis.

The authors concluded:

"Over-expression of DNA repair genes (predominantly those involved in doublestrand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability."

In the past, we have discussed synthetic lethality and DNA repair on this blog in breast and ovarian cancers, with respect to PARP inhibitors seeking to repair damaged DNA and prolong survival outcomes. Based on the current analysis, it looks as though a similar approach may be useful in melanoma. This may give clues for future pipeline development of new therapeutics designed to tackle the specific underlying biology of the cancer.

It should be noticed, though, that the results are describing the factors contributing to relapse from chemotherapy (dacarbazine, DTIC) rather than current pipeline drugs in development for melanoma such as PLX-4032 (Roche/Plexxikon) or ipilimumab (BMS).

I would be very interested to see whether the biomarkers identified in this research for chemotherapy would also apply to the targeted therapies. It is possible that they may not, or possibly they could help reverse or repair some of the changes occurring. Either way, finding ways to address the DNA repair may be a fruitful area of study.

Jewell, R., Conway, C., Mitra, A., Randerson-Moor, J., Lobo, S., Nsengimana, J., Harland, M., Marples, M., Edward, S., Cook, M., Powell, B., Boon, A., de Kort, F., Parker, K., Cree, I., Barrett, J., Knowles, M., Bishop, T., & Newton-Bishop, J. (2010). Patterns of Expression of DNA Repair Genes and Relapse from Melanoma Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-10-1521

Circulating IGF-I levels and pancreatic cancer risk

By MaverickNY on August 16, 2010

A couple of new papers will be reviewed this week, thanks to everyone who sent in links and suggested topics for discussion. I'll try and cover one a day, although there were so many worthy of consideration! Please do keep the ideas coming, they are much appreciated.

For today, here's one I came across last week in one of the American Association of Cancer Research (AACR) journals, Cancer epidemiology, biomarkers & prevention. The article discusses the evidence surrounding overexpression of insulin-like growth factor (IGF)-I and how that is implicated in human pancreatic tumours. To look at this concept further, the researchers decided to use longitudinal data from a study involving 187 cases and 374 controls, a not insignificant number as a starting point:

"We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic circulating IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk."

For those needing some background, I've covered the IGF pathway and some of the therapeutic inhibitors being developed in cancer before (see here, here, here and here for examples).

Michael Pollak, one of the authors from McGill University in Montreal, is a recognised authority on the subject and gave a fascinating talk on the science and biology behind the topic at the AACR Lung cancer meeting back in January this year. It's a particularly interesting pathway, not only because of the potential for cross-talk between pathways, but also feedback and feedforward loops, especially with the insulin receptor (IR), as Pollak elegantly illustrated.

It was therefore with great curiousity that I downloaded and read the paper (see the clickable journal link in the reference below), wondering what they found in the broader study. Essentially, they concluded that:

"A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which may be a risk factor for pancreatic cancer."

Thus, rather than the absolute levels per se, the ratio may turn out to be a useful biomarker of the disease because the individual levels were not found to be helpful by the researchers, who:

"confirmed the nonsignificant associations for IGF-I, IGF-II, and IGFBP- 3 and risk of pancreatic cancer from previous studies."

As many of you know, pancreatic cancer is rather nasty, typically being diagnosed late because the symptoms can be subtle to detect and diffential diagnosis from other conditions associated with general malaise is hard. A new biomarker would be clearly be helpful, although the findings will need to be validated in future large scale longitudinal studies or from pooled analysis from other prospective trials.

Mind you, this research on pancreatic cancer reminded me of the phase I Merck study in the same tumour type, reported earlier this year, with a combination of different therapies including IGF-1R and EGFR inhibitors.

As far as I can remember, Merck also included the use of metformin in the protocol to manage hyperglycemia, which would also potentially block the IGF-1R – IR feedback loop seen in the figitumumab trial. Still, it would be interesting to know whether the IGF-I/IGFBP-3 molar ratio and free IGF were higher in the people with pancreatic cancer in that study.

Clearly, if IGF-I/IGFBP-3 turns out to be a valid biomarker of disease risk then it may be possible to identify, monitor and ultimately treat people with pancreatic cancer earlier, as well as develop better pipeline drugs, since we learn more about the biology of the disease in the process.

That can only be a great thing in the long run for improved outcomes.

Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, & Stolzenberg-Solomon RZ (2010). Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699371

Pathwork Diagnostics and Novartis to pursue a research partnership

By MaverickNY on July 30, 2010

It was interesting to see my Diagnostics alert feed full of the news that Pathwork Diagnostics and the new Novartis molecular diagnostics group are entering a research partnership.

I first came across Pathwork Dx at ASCO last month when they presented an interesting poster on their tissue of origin gene based expression test to help in the diagnosis of poorly differentiated and metastatic tumours. Clearly, an accurate diagnosis will lead to better optimisation of appropriate therapy and risk assessment/management. The tissue based test has since received approval from the FDA.

According to Pathwork:

"The Tissue of Origin LDT uses a combination of microarray technology and advanced analytics to measure the gene expression patterns (comprising more than 1500 genes) of challenging tumors, including poorly differentiated, undifferentiated, and metastatic cancer. These data are compared with the gene expression patterns of a panel of 15 known tissue types—representing 58 morphologies and covering 90% of solid tumors—in order to identify the tumor."

The tissue test is based on gene arrays using DNA and RNA technology used in research, but with its approval, we will start to see more commercial applications evolve for diagnostic purposes.

More details about the deal and the financial background can be found in the WSJ.

What's interesting here is that:

1) We are seeing more sophisticated technology emerge for both tissue and blood biomarkers, which will hopefully help us improve not only diagnosis but also treatment and monitoring of drug responses over time.

2) More integration and collaborations between manufacturers and diagnostic companies means that the information and knowledge can be shared more easily and quickly rather than being bogged down in silos.

3) The companies that do well with integrating diagnostics into their cancer programs will not only have a huge commercial edge, but it will continue to raise the bar for new competitors and smaller companies in terms of funding and resources.

It's going to be fascinating watching this area of oncology develop.

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Abnormal Circulating Cells in Lung Cancer Patients: Possible New Technique for Identification

By MaverickNY on July 27, 2010

A while back I wrote about how circulating tumour cells (CTC’s) see here and here, can be used as a potential new surrogate measure for prostate cancer, so it was with great interest that I read an excellent article (free public link courtesy of AACR) on abnormal circulating cells in non-small cell lung cancer (NSCLC) late last week.

Essentially, this new research from three academic institutions (MD Anderson TX, Manchester UK and Baltimore, MD) set out to:

“Determine if a fluorescence in situ hybridization (FISH)–based assay using isolated peripheral blood mononuclear cells (PBMCs) with DNA probes targeting specific sites on chromosomes known to have abnormalities in non–small cell lung cancer (NSCLC) cases could detect circulating genetically abnormal cells (CACs).”

In the recent discussion about fluid-based blood biomarkers, we saw how people could be spared invasive and inconvenient tumour biopsies, which are not always practical in advanced lung cancer, particularly if the patient is elderly or frail. In this study, the researchers demonstrated that detection of circulating epithelial cells (CECs) or CTCs using a simple blood test may assist in early detection of lung cancer at diagnosis and relapse and provide a minimally invasive way to monitor results of therapy.

Now in this study, only a small number of people with NSCLC were evaluated (NSCLC n=59 plus n=29 controls), but they do give us an indication of what could be looked at in larger scale clinical trials (first find your needle in the haystack!) The presence or increased numbers of these circulating abnormal cells confers a poorer prognosis, ie associated with relapse of disease and poorer survival, so the ability to pick them up earlier and more easily would be an advantage clinically.

The approach used in this research was a commonly used technique called fluorescence in situ hybridization (FISH) to detect abnormal circulating cells that have aberrations found in non-small cell lung cancer. FISH detects and quantifies abnormal cells by using dye-labeled DNA probes of cell chromosomes that cause cells with the targeted genetic abnormalities to light up when viewed under a fluorescent microscope.

The researchers chose 12 biomarker probes that target aberrations previously connected to lung cancer to analyze both the controls (people without lung cancer) and people with NSCLC, including both smokers and non-smokers. In the analysis they found the following:

Highly significant differences in the average number of abnormal cells in the bloodstream between patients and controls.
Abnormal cells were significantly associated with disease stage, with cells that contained certain abnormalities increasing significantly as cancer progressed from early to advanced stage disease.
Eight of the biomarkers had a strong overall correlation between abnormal circulating cells and tumors. Chromosomal gain of the EGFR gene in circulating cells was significantly associated with the same gain in tumors, particularly in patients with stage III or stage IV disease.

No doubt work will soon be underway to develop a commercial clinical test based on FISH, which would then be able to be used in the Community Oncology setting, where the majority of patients are treated in the US. Validation in clinical trials will be crucial to this process.

In an MD Anderson news release, the lead author, Ruth Katz, was quoted as saying:

“Blood tests for these circulating tumor cells could be used to diagnose lung cancer earlier, monitor response to therapy and detect residual disease in patients after treatment.”

Source: MD Anderson Cancer Center

Having an easier to use test to monitor responses more accurately to products in development will be particularly useful for pipeline drugs.

References:

Katz, R., He, W., Khanna, A., Fernandez, R., Zaidi, T., Krebs, M., Caraway, N., Zhang, H., Jiang, F., Spitz, M., Blowers, D., Jimenez, C., Mehran, R., Swisher, S., Roth, J., Morris, J., Etzel, C., & El-Zein, R. (2010). Genetically Abnormal Circulating Cells in Lung Cancer Patients: An Antigen-Independent Fluorescence In situ Hybridization-Based Case-Control Study Clinical Cancer Research, 16 (15), 3976-3987 DOI: 10.1158/1078-0432.CCR-09-3358

The Long Tail of Cancer Research

By MaverickNY on July 14, 2010

"What's really amazing about the Long Tail is the sheer size of it. Combine enough nonhits on the Long Tail and you've got a market bigger than the hits."

Source: Chris Anderson, Wired

The other other day, while barely lucid in the early hours of the morning, I was thinking about the herd instinct, the tendency to follow the masses and the counterpoint to that, i.e. the long tail.

If you're wondering what the long tail is, think of those statistical distribution plots where everything is bunched around the median, creating 50% on one side and 50% on the other. At either end the plots tail off into infinity. That's the long tail.

The long tail looks small at first, but creative marketers realise that added up (as Chris Anderson's quote above shows), you can in effect still have quite a large niche market while every one else focuses on minute shares in the middle.

I first realised the long tail effect as a sales rep in the tough anti-cholesterol market. You can spend fruitless hours chasing the majority of the primary care doctors who see reps but don't remember you when the relevant patient appears, or you can carefully invest time in the ones who don't see reps but are busy with appropriate patients and eventually crack if you try enough times. Once convinced, they often switch wholesale and your job is done with a smaller group of physicians who others can't see :-).

If we apply the principle of the long tail to cancer research, we can see things more clearly. In the old days, the majority of patients got treated pretty much the same with various chemo doublets, irrespective of whether they might work or not. In fact, in many cases, there wasn't even biomarkers such as ERCC1 to determine which patient should get platinum or not, but things are changing and now it's much easier to make these decisions and start segmenting patients according to their biochemical profile and make decisions based on the profile.

Today, we can take this niche idea to treatment a lot further.

In colon cancer, for example, we now know that patients with wild type KRAS are more likely to respond to an EGFR therapy than those with mutant KRAS. However, in lung cancer, the old adage was that erlotinib (Tarceva) was best suited for patients who were female, asian, non-smokers with adenocarcinoma is giving way to a more precise definition, i.e. do they have the EGFR mutation or not? If they do, they're more likely to respond, irrespective of smoking status. Offering these patients maintenance treatment may also be an effective treatment strategy that impacts outcomes.

We can see this effect in other cancer types too. Trastuzumab (Herceptin) is approved for women with Her-2 breast cancer, imatinib (Gleevec) and other TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna) for Philadelphia-chromosome positive chromic myeloid leukemia (CML).

Histology is a very crude way to select patients, but looking at the aberrant mutations essentially creates niche long tail opportunities to treatment for pharma and biotech companies. Patients who are more likely to respond to a given therapeutic get appropriate treatment, without having to expose others who would not to unnecessary systemic effects. This is a win-win solution all around.

Why?

Well, it's good news for patients as you increase the chances of successful outcomes rather than relying on hope alone. It's also good news for manufacturers because smaller patient populations ultimately involve fewer patients in clinical trials, thereby making clinical development more cost effective and as cancer therapy moves from an acute to chronic disease, so longer term revenues are generated despite a small patient base.

As more oncology companies start looking at their pipelines, we can see many asking the critical questions – which patients are more likely to respond to a given treatment and why? As we learn more about the underlying biology of the disease, so companion diagnostics are also evolving in sophistication and sensitivity.

The other marketing advantage of developing niche targeted therapies and diagnostics is that often, you see less competition for smaller subsets of disease because it creates a high barrier to entry. Diagnostics also create barriers to entry because of the extra costs involved in their development. For smaller biotechs this can be prohibitive, and many are more actively seeking Pharma and Biotech partners to fund late stage research and clinical trials. Overall, the long tail opportunities offer big and small hurdles, depending on the circumstances.

Roche's VEGF monoclonal antibody bevacizumab (Avastin) has a very high barrier to entry in colon cancer, for example, as other VEGF inhibitors have fallen by the wayside, unable to beat the results already obtained by the first to market drug.

At the other end of the scale, the barrier to entry is much lower in renal cell cancer with numerous targeted therapies now approved for a relatively small niche indication, including sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), pazopanib (Votrient) and bevacizumab (Avastin), probably reflecting the improvement over IL2, without completely reducing unwanted side effects or dramatically improving efficacy.

Some of the marketed therapies mentioned in this post are now billion dollar blockbusters despite cancer being a relatively niche market opportunity compared to the much bigger primary care markets such as metabolic or cardiovascular disease, proving that there are valuable nuggets to be found, even in the long tail.

The future in cancer research is not in broad acting systemic chemotherapies that target normal cells as well as cancer cells, but in the niche development of better and less toxic targeted therapies based on the underlying biological abnormalities with easy to use diagnostic technology based on fluid-based biomarkers. To achieve this though, will take a lot of bright smart people with expertise in oncology who dare to think differently and boldly, whether they be scientists, marketers or clinical research professionals.

Watch this space!

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Fluid-based early detection biomarkers in cancer

By MaverickNY on July 13, 2010

A really interesting idea that seems to be growing in popularity is the concept of fluid-based biomarkers from blood, urine, saliva etc, as opposed to invasive tumour biopsies. A recent paper in Cancer Research took a look at this novel and much needed concept (reference below).

One of the biggest challenges in oncology at the moment is finding easier and more convenient ways of identifying appropriate patients who might be best suited for a given therapy. In clinical trials, often tests are developed as useful biomarkers based on tumour biopsies. However, once a drug is approved, Community Oncologists often find their patients older, frailer and with a poorer performance status or more advanced disease and thus unresectable. Earlier detection of asymptomatic patients would also be useful, since in general, the earlier the patient is diagnosed, the better their long term chances are.

There is a lot of potential value, therefore, in developing fluid-based biomarkers and tests since the majority of cancer patients are treated in the Community, rather than Academic, setting.

In leukemias, FISH and QT-PCR testing have become standard, largely because it is easy to compare a blood sample with that of a bone marrow sample to validate test results. In solid tumours though, that has generally been less easy. Even the FISH test for HER-2 positive women with breast cancer has not been without it's controversies over the years.

At recent cancer meetings such as ASCO and AACR, I have noticed an increasing number of early surrogate markers being explored in solid tumours such as circulating tumour cells (CTCs) in prostate cancer as a more viable marker than PSA, as the authors also discussed:

"Fluid sampling has advantages over imaging as it is widely accepted, readily repeated, convenient, noninvasive, and low cost. Biomarkers in body fluids have the potential to detect a wide variety of primary tumors and metastases located throughout the body. Fluid biomarkers include a variety of components in blood, urine, or other fluids that reflect the presence of a tumor in the body. These include circulating tumor cells (CTC) and macromolecules such as lipids, proteins, RNA, microRNA, and DNA that originate from tumor cells."

Source: Martin et al.,

It was interesting to see the development of Pfizer's crizotinib in non-small cell lung cancer (NSCLC) with ALK mutations emerge recently. While Pfizer should be applauded for the speed with which they have developed the drug after the mutation was discovered, the development of the mutation test has clearly not been without its challenges.

A number of patient blogs complained about the time taken to produce the results from the tumour biopsies (several weeks to a month compared to say, 48 hrs for blood tests) and also in some cases, that their own physician ordered tests were not accepted, requiring another test validated by a central laboratory, sometimes with differing results. This does not augur well for an easy to use commercial diagnostic test for ALK if there are variations in the results.

Patients with advanced lung cancer often don't have a lot of time so this will be an issue to them and their physicians. Part of the reason for the delay is that tumour biopsy tests often require DNA sequencing to be performed, which inevitably takes time. A validated blood test would have a huge advantage in terms of time and convenience, but whether it is practically possible in an example like this, I don't know.

Whether a validated blood test is being developed in parallel isn't yet clear, but lung biopsies in the community setting are not routine in the way they are for breast cancer, for example. Finding suitable patients will therefore be akin to looking for needles in a haystack as the data so far suggests that the number of patients who were ALK positive in the NSCLC trials that looked for the mutation was around 5%. I'm not sure if this will extrapolate to the broader lung cancer universe though, as patients in a clinical trial are typically different from those in the general cancer population.

Meanwhile, another other interesting trend that is emerging is microRNA:

"In addition to proteins, mRNAs are promising biomarkers, and microarrays represent a powerful approach for their discovery in blood. A study using custom spotted arrays published in 2001 identified a signature of 12 genes whose mRNA expression was elevated in peripheral blood mononuclear cells (PBMC) of breast cancer patients."

Source: Martin et al.,

The number of articles, papers, abstracts and presentations on microRNA has increased at a tremendous rate over the last 2 years. At the AACR Molecular Targets meeting last November, it seemed as though 1 in 3 abstracts mentioned the subject in a variety of different ways from prognosis to early resistance. This is one area I'll be following to see what interesting new concepts emerge. I've had a few requests for more information on microRNA, so this will be the topic of a forthcoming blog post.

The ultimate question as always, though, is what does this all mean?

Clearly, earlier detection of disease is useful for prognosis, but predicting the impact of therapeutic intervention is also important. If we can develop biomarkers for determining which drug might work optimally for a given patient or subset, that would alleviate a lot of the pressure on healthcare systems and reducing patient exposure to drugs that would not work. At present, there are probably more tests developed than actually used in practice, but incorporating them into large scale clinical trials as part of a battery of tests may well provide more useful information in the near future across a variety of different cancer types.

Time will tell, but it makes a lot of sense to incorporate a vast battery of surrogate biomarker tests upfront and then track what happens over time, as the Medivation trial with MDV3100 has shown with PSA and CTC's in prostate cancer, to offer a practical example. You never know which of the biomarkers tested will emerge as useful in any given tumour type, so testing more rather than fewer may have a higher chance of hitting the bullseye.

Martin, K., Fournier, M., Reddy, G., & Pardee, A. (2010). A Need for Basic Research on Fluid-Based Early Detection Biomarkers Cancer Research, 70 (13), 5203-5206 DOI: 10.1158/0008-5472.CAN-10-0987

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Advancing the Use of Biomarkers in Cancer Drug Development

By MaverickNY on July 1, 2010

This was the title of a fascinating article I saw on Twitter a few minutes ago, courtesy of the American Association of Cancer Research (AACR). They are providing access to the paper free of charge to the public using this link. If you are on Twitter and interested in cancer related research, do follow them and keep track of the hot news items as they share quite a few important articles on translational research. Of all the medical associations I've come across in social media, they are also very helpful and responsive to enquiries.

So, what of the Consensus Report? Well, it's a collaborative effort from the AACR, FDA and NCI to create a position statement of the state of play so far:

"There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost."

As always, though, things are never as easy or simple as one might like.

Developing novel and useful biomarkers is an expensive and time consuming process driven largely by translational research and bioinformatics, often with a lot of diverse stakeholders involved in the process.

The Cancer Biomarkers Collaboration covered recommendations in eight key areas:

Biospecimens
Analytical performance
Standardisation and harmonisation
Bioinformatics
Collaboration and data sharing
Regulatory issues
Stakeholder education and communication
Science policy

Ultimately, the goal of the collaboration is to:

"The AACR-FDA-NCI Cancer Biomarkers Collaborative is a stakeholder-driven effort to inform and accelerate the FDA Critical Path Initiative and the work of the broader cancer
community."

The paper is well worth reading for those interested in the area, so check it out.

Meanwhile, on a practical note, a new potential biomarker has emerged in small cell lung cancer (SCLC) – see link to the Journal of Thoracic Oncology below (subscription required). The problem here is that while the majority of people with SCLC initially respond well to chemotherapy, resistance develops leading to relapse. The big question is why?

To answer this question, the researchers hypothesised that:

"… tumor microRNAs (miRNAs) could serve as predictive biomarkers for chemoresistance and prognostic biomarkers for survival of patients with SCLC treated with systemic chemotherapy."

The initial microRNA research on tumour samples (n=34) showed that:

"Higher tumor miR-92a-2* levels are associated with chemoresistance and with decreased survival in patients with SCLC.
Tumor miR-92a-2* may have application in screening patients with SCLC at risk for de novo chemoresistance in an effort to design more tailored clinical trials for this subpopulation."

In other words, microRNA (miR-92a-2*) could potentially be used as both a predictive and prognostic marker in SCLC. These results will need to be validated in larger scale trials, but they offer a promising glimpse of what might be possible for future therapeutic interventions.

Khleif, S., Doroshow, J., Hait, W., et al., (2010). AACR-FDA-NCI Cancer Biomarkers Collaborative Consensus Report: Advancing the Use of Biomarkers in Cancer Drug Development Clinical Cancer Research, 16 (13), 3299-3318 DOI: 10.1158/1078-0432.CCR-10-0880

Ranade, A., Cherba, D., Sridhar, S., Richardson, P., Webb, C., Paripati, A., Bowles, B., & Weiss, G. (2010). MicroRNA 92a-2* Journal of Thoracic Oncology DOI: 10.1097/JTO.0b013e3181dea6be

Tumour associated macrophages and survival in Hodgkins Lymphoma

By MaverickNY on March 15, 2010

While reading my pile of mail on Friday, I realised that an interesting paper on Hodgkins Lymphoma (HL) appeared in the current edition of the New England Journal of Medicine (full reference below).

The basics of the paper are that despite advances in HL, including curative radiation in the early stages if the disease, one third of patients with advanced disease and about 15% of those with early disease have a relapse after treatment. 20% of people still die from the disease.

The question is why?

Well, unfortunately, current prognostic models have not been shown to be very accurate and so far, no biomarker has been found to be particularly useful.

The authors set out to use gene-expression profiling obtained from people with HL during diagnostic lymph node biopsy to determine which signatures were correlated with treatment. They confirmed their findings with an independent cohort of 166 patients using standard immunohistochemical analysis.

What they found was fascinating:

A gene signature of of tumour associated macrophages was associated with primary treatment failure.
An increased number of CD68 macrophages correlated with likelihood of relapse after autologous stem cell transplantation.
The adverse prognostic factor (macrophages) outperformed the current International Prognostic Score for disease-specific survival.
The absence of an elevated number of CD68+ cells in patients with limited stage disease defined a sub-group of patients with long-term disease specific survival of 100% with the current therapies.

When I was at school, we learned that macrophages were associated with an immune response to invasion. According to the NEJM Editorial, by DeVita and Costa, this may not be the case:

"Most of the evidence, however, now links the presence of tumor-associated macrophages with a poor prognosis."

In short, the data shows that increased number of tumour associated macrophages was strongly associated with shortened survival in HL and provides a biomarker for prognosis and risk stratification. What does this all mean though, for clinical practice?

DeVita and Costa noted that:

"If at the time of diagnosis we could identify patients who are destined to have a poor response to treatment, most patients could be spared a combination of therapies or radiotherapy with its attendant long-term toxic effects."

This is an important observation alone.

For the future, though, the data suggests some new directions that clinical research could go in, such as an anti-CD68 monoclonal antibody perhaps. There are some that have been identified for rheumatoid arthritis (RA) as the Kunisch paper shows below, but I don't think any are currently in commercial development at the moment.

For the moment, though, I'm left wondering more than there are answers.

Why do people with macrophages do worse, what is the mechanism for this? How can we best target the macrophages or the CD68 cells? If people are screened and are found to have a poorer prognosis and are spared the exposure to chemotherapy or radiation as DeVita and Costa suggest, how should they be treated instead?

Perhaps more research will be galvanised by Steidl et al's findings. Time will tell.

Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, & Gascoyne RD (2010). Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. The New England journal of medicine, 362 (10), 875-85 PMID: 20220182

DeVita, V., & Costa, J. (2010). Toward a Personalized Treatment of Hodgkin's Disease New England Journal of Medicine, 362 (10), 942-943 DOI: 10.1056/NEJMe0912481

Kunisch, E. (2004). Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry Annals of the Rheumatic Diseases, 63 (7), 774-784 DOI: 10.1136/ard.2003.013029

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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘biomarkers’